Codeine

(5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol

Overview

Codeine belongs to Opioids.

Key safety note: Codeine's analgesia and toxicity depend heavily on CYP2D6 genotype: ultra-rapid metabolizers can develop life-threatening respiratory depression at ordinary doses, which is why it is contraindicated in young children and while breastfeeding.[4][5]
Effects
Subjective effects vary. What a substance feels like depends on dose, individual physiology, mindset, and setting. The points below describe commonly reported effects, not guaranteed, uniform, or desirable outcomes.
  • At therapeutic doses: mild-to-moderate analgesia and cough suppression, commonly with drowsiness, nausea and constipation.
  • At higher (recreational) doses: opioid euphoria, warmth, relaxation and itching, alongside pronounced sedation, pinpoint pupils and slowed breathing.
  • Effects begin ~30–45 minutes after an oral dose and last around 4–6 hours. A euphoric 'ceiling' is reached near ~400 mg, beyond which side effects, not pleasant effects, increase.
Dosing & duration
Harm-reduction note: These are commonly cited reference ranges, not a recommendation or a “safe” dose. Potency, purity, body chemistry, tolerance, and drug combinations vary widely. Start low, go slow, wait for full effects before redosing, and never assume an unknown product matches these figures. Missing data is not evidence of safety.

Oral (tablets, capsules or liquid/cough syrup). Medical use is oral only. The figures below are commonly cited recreational oral reference ranges, not a recommendation or a 'safe' dose. Codeine is a prodrug whose effect depends on CYP2D6 genotype, so the same dose can do little in one person and cause dangerous respiratory depression in another. Critically, recreational doses of codeine combination products deliver toxic amounts of the co-formulated paracetamol/acetaminophen, ibuprofen or promethazine: a 'recreational' codeine dose taken this way can be lethal from paracetamol-induced liver failure long before the codeine itself. Cold-water extraction does not make this reliably safe.

Dose ranges

Threshold

30 mg

Light

50–100 mg

Common

100–150 mg

Strong

150–200 mg

Heavy

200 mg +

Duration

onset

30–45 minutes

total

3–6 hours

after effects

Sedation and constipation. Tolerance and physical dependence with repeated use

Chemical & Physical Properties
FormulaC18H21NO3
Molar mass299.36 g/mol
StateSolid
Melting point157.5 °C
Boiling point250 °C at 22 mmHg
Density1.32 g/cm³ at 20 °C (NTP, 1992)
Vapor pressureNot reported
pKa8.2
LogP1.39
Solubilityless than 1 mg/mL at 21 °C (NTP, 1992), soluble in water, Slightly soluble in water
Refractive indexNot reported
Identifiers & Synonyms
CAS76-57-3
CAS (enantiomer)
PubChem CID5284371
InChIKeyOROGSEYTTFOCAN-DNJOTXNNSA-N
InChIInChI=1S/C18H21NO3/c1-19-8-7-18-11-4-5-13(20)17(18)22-16-14(21-2)6-3-10(15(16)18)9-12(11)19/h3-6,11-13,17,20H,7-9H2,1-2H3/t11-,12+,13-,17-,18-/m0/s1
SMILESCN1CC[C@]23[C@@H]4[C@H]1CC5=C2C(=C(C=C5)OC)O[C@H]3[C@H](C=C4)O

Synonyms

  • Methylmorphine
  • Codeine
  • 3-methylmorphine
Pharmacodynamics & Biochemistry

Codeine is a comparatively weak μ-opioid (MOR) agonist in its own right. Much of its analgesic effect comes from being a prodrug. Roughly 5–10% of a dose is O-demethylated by the liver enzyme CYP2D6 to morphine, a far more potent MOR agonist, so codeine largely serves as a delivery form for morphine. Agonism at μ-opioid receptors in the CNS produces analgesia, sedation, euphoria and miosis, depresses the brainstem respiratory centres, and suppresses the medullary cough reflex (the basis of codeine's antitussive use), while peripheral MOR activation in the gut slows motility and causes constipation. Because the morphine conversion depends on CYP2D6, a highly genetically variable enzyme, response is unpredictable: poor metabolizers obtain little analgesia, whereas ultra-rapid metabolizers generate excess morphine and can develop life-threatening respiratory depression at ordinary doses.

Biological targets

  • MOR

Binding & functional measurements

TargetMeasurementSpecies
μ-opioid receptorKi 734 nMHuman
δ-opioid receptorKi 5,500 ± 600 nMRat
μ-opioid receptorKi 152 ± 33 nMGuinea pig
μ-opioid receptorKi 1,300 ± 500 nMRat
Pharmacokinetics
BioavailabilityOral ≈50%
Tmax≈1 h
Half-life≈3 h
VdNot reported
Protein bindingNot reported
MetabolismHepatic CYP2D6 to morphine (~10%). Glucuronidation to codeine-6-glucuronide
ExcretionRenal
Toxicology & Safety
Harm-reduction note: Toxicity and risk depend on dose, route, purity, combinations, setting, and individual health factors. Missing harms should never be interpreted as evidence of safety.

Not reported

Codeine's analgesia and toxicity depend heavily on CYP2D6 genotype: ultra-rapid metabolizers can develop life-threatening respiratory depression at ordinary doses, which is why it is contraindicated in young children and while breastfeeding. Like all opioids it can cause fatal respiratory depression, especially combined with alcohol, benzodiazepines or other depressants, and it produces tolerance and physical dependence. A distinct, often-overlooked hazard is that recreational use of combination products can deliver toxic doses of the co-formulated paracetamol/acetaminophen, ibuprofen or promethazine. Cold-water extraction does not make this reliably safe.[4][5]

Legal Status
Legal note: Legal status can change over time and may vary by country, region, formulation, analogue status, prescription context, and enforcement practice. Always confirm with current official sources before relying on this section.
Interactions & Contraindications

Drug interactions

Alcohol, Benzodiazepines, Opioids, Gabapentinoids (gabapentin, pregabalin) Additive sedation and respiratory depression, the main mechanism of opioid overdose death.[4][3]
Strong CYP2D6 inhibitors (e.g. paroxetine, fluoxetine) Fluoxetine, paroxetine, bupropion, quinidine or some antihistamines (e.g. diphenhydramine) block conversion to morphine and reduce analgesia.[5][8]
MAOIs, SSRIs, SNRIs, Tramadol Risk of serotonin syndrome, and MAOIs risk severe opioid potentiation.[4][3]
Co-formulated paracetamol/acetaminophen or ibuprofen (combination analgesics) Co-formulated paracetamol/acetaminophen or ibuprofen has its own dose ceiling, and exceeding it to chase the codeine risks hepatotoxicity or GI/renal harm.[4][6]

Contraindications

Children (age-restricted; respiratory-depression risk) children under 12, and post-tonsillectomy or adenoidectomy in those under 18.[5][4]
CYP2D6 ultra-rapid metaboliser status[5]
Pregnancy or breastfeeding breastfeeding (morphine passes into breast milk).[5]
Significant respiratory depression or acute severe asthma or acute/severe bronchial asthma in an unmonitored setting.[4][3]
Concurrent MAOI, SSRI/SNRI or other serotonergic medication concurrent MAOI use.[3]
Paralytic ileus or gastrointestinal obstruction paralytic ileus.[3]
Usage & Context
  • Widely used medically as a mild-to-moderate analgesic, usually combined with paracetamol/acetaminophen or an NSAID, and as an antitussive.
  • Misused recreationally for opioid euphoria, frequently from over-the-counter or prescription cough-and-cold combination products. The codeine-plus-promethazine cough-syrup mixture is known as 'lean' or 'purple drank'.
  • One of the most widely prescribed opioids worldwide and a common entry point to opioid misuse and dependence.
Sources & Evidence
  1. Toll L, Berzetei-Gurske IP, Polgar WE, et al. (1998). Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. NIDA Res Monogr 178:440-66.

    PMID 9686407

  2. PubChem: Codeine (CID 5284371) — identifiers & computed properties
  3. FDA / DailyMed: Codeine prescribing information — pharmacokinetics & metabolism
  4. Patel P, Tharp JG, Eriator II, Rout P. Codeine. StatPearls [Internet] (NCBI Bookshelf, NBK526029) — pharmacology, medical use & toxicity
  5. Crews KR, Gaedigk A, Dunnenberger HM, et al. (2014). Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther 95:376-82.

    PMID 24458010 · doi:10.1038/clpt.2013.254

  6. Wikipedia: Codeine (pharmacology, pharmacokinetics, effects & legal status) CC BY-SA 4.0
  7. IUPHAR/BPS Guide to PHARMACOLOGY: codeine (ligand 1673) — μ-opioid receptor binding data CC BY-SA 4.0
  8. PsychonautWiki: Codeine — recreational dosage & duration CC BY-SA 4.0
  9. DEA Diversion Control Division: Controlled Substance Schedules (codeine single-agent is Schedule II)
  10. GOV.UK: Controlled drugs list (Misuse of Drugs legislation) — codeine is Class B OGL v3.0
  11. Anlage III BtMG — Betäubungsmittelgesetz (codeine listing & low-dose exemptions)
  12. Volpe DA, McMahon Tobin GA, Mellon RD, et al. (2011). Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol 59:385-90.

    PMID 21215785 · doi:10.1016/j.yrtph.2010.12.007

  13. Tzschentke TM, Christoph T, Kögel B, et al. (2007). (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther 323:265-76.

    PMID 17656655 · doi:10.1124/jpet.107.126052

Further Information